Microdosing for drug delivery application—A review

There is an increasing amount of research on microfluidic actuators with the aim to improve drug dosing applications. Micropumps are promising as they reduce the size and energy consumption of dosing concepts and enable new therapies. Even though there are evident advantages, there are only few examples of industrial microdosing units and micropump technology has not yet found widespread application. To answer the evoked question of what limits the application of microdosing technology for drug delivery, this work provides a comprehensive insight into the subject of drug dosing. We highlight and analyse specific microfluidic challenges and requirements in medical dosing: safety relevant aspects, such as prevention of freeflow and backflow; dosing-specific requirements, such as dosing precision and stability; and system-specific aspects, such as size, weight, and power restrictions or economic aspects. Based on these requirements, we evaluate the suitability of different mechanical micropumps and actuation mechanisms for drug administration. In addition to research work, we present industrial microdosing systems that are commercially available or close to market release. We then summarize outstanding technical solutions that ensure sufficient fluidic performance, guarantee a safe use, and fulfil the specific requirements of medical microdosing

Micro Electromechanical Systems (MEMS) Based Microfluidic Devices for Biomedical Applications

Micro Electromechanical Systems (MEMS) based microfluidic devices have gained popularity in biomedicine field over the last few years. In this paper, a comprehensive overview of microfluidic devices such as micropumps and microneedles has been presented for biomedical applications. The aim of this paper is to present the major features and issues related to micropumps and microneedles, e.g., working principles, actuation methods, fabrication techniques, construction, performance parameters, failure analysis, testing, safety issues, applications, commercialization issues and future prospects. Based on the actuation mechanisms, the micropumps are classified into two main types, i.e., mechanical and non-mechanical micropumps. Microneedles can be categorized according to their structure, fabrication process, material, overall shape, tip shape, size, array density and application. The presented literature review on micropumps and microneedles will provide comprehensive information for researchers working on design and development of microfluidic devices for biomedical applications

HIGH PERFORMANCE PIEZOELECTRIC MATERIALS AND DEVICES FOR MULTILAYER LOW TEMPERATURE CO-FIRED CERAMIC BASED MICROFLUIDIC SYSTEMS

The incorporation of active piezoelectric elements and fluidic components into micro-electromechanical systems (MEMS) is of great interest for the development of sensors, actuators, and integrated systems used in microfluidics. Low temperature cofired ceramics (LTCC), widely used as electronic packaging materials, offer the possibility of manufacturing highly integrated microfluidic systems with complex 3-D features and various co-firable functional materials in a multilayer module. It would be desirable to integrate high performance lead zirconate titanate (PZT) based ceramics into LTCC-based MEMS using modern thick film and 3-D packaging technologies. The challenges for fabricating functional LTCC/PZT devices are: 1) formulating piezoelectric compositions which have similar sintering conditions to LTCC materials; 2) reducing elemental inter-diffusion between the LTCC package and PZT materials in co-firing process; and 3) developing active piezoelectric layers with desirable electric properties. The goal of present work was to develop low temperature fired PZT-based materials and compatible processing methods which enable integration of piezoelectric elements with LTCC materials and production of high performance integrated multilayer devices for microfluidics. First, the low temperature sintering behavior of piezoelectric ceramics in the solid solution of Pb(Zr0.53,Ti0.47)O3-Sr(K0.25, Nb0.75)O3 (PZT-SKN) with sintering aids has been investigated. 1 wt% LiBiO2 + 1 wt% CuO fluxed PZT-SKN ceramics sintered at 900oC for 1 h exhibited desirable piezoelectric and dielectric properties with a reduction of sintering temperature by 350oC. Next, the fluxed PZT-SKN tapes were successfully laminated and co-fired with LTCC materials to build the hybrid multilayer structures. HL2000/PZT-SKN multilayer ceramics co-fired at 900oC for 0.5 h exhibited the optimal properties with high field d33 piezoelectric coefficient of 356 pm/V. A potential application of the developed LTCC/PZT-SKN multilayer ceramics as a microbalance was demonstrated. The final research focus was the fabrication of an HL2000/PZT-SKN multilayer piezoelectric micropump and the characterization of pumping performance. The measured maximum flow rate and backpressure were 450 μl/min and 1.4 kPa respectively. Use of different microchannel geometries has been studied to improve the pumping performance. It is believed that the high performance multilayer piezoelectric devices implemented in this work will enable the development of highly integrated LTCC-based microfluidic systems for many future applications

Integration technologies for implantable microsystems

Microsystems targeted for implantation require careful consideration of power, thermals, size, reliability, and biocompatibility. The presented research explored appropriate integration technologies for an implantable drug delivery system suitable for use in mice weighing less than 20 grams. Microsystems technology advancements include in situ pump diaphragm formation; integrated, low volume microfluidic coupling technologies; and incorporation of a low voltage, low-power pump actuation with a zero-power off state. Utility of the developed integration technologies have been tested through in vitro reliability and validation experiments. A four-chamber peristaltic pump was created using micromachining (e.g. thin film deposition and Si etching) and direct write techniques. A novel phase change material based actuator was designed and fabricated to deflect deformable diaphragms into and out of four pump chambers while the diaphragms isolated the pumped fluid from the working material. Polyimide capillary tubing with 140-μm OD was integrated in-plane and acted as fluidic interconnects to a drug supply and to the pharmaceutical delivery site. Parylene C conformal coating and the design for gap occlusion provided sealed, flexible tubing connections to the micropump. The per chamber actuation power of 10.1 mW at 0.083 Hz resulted in fluid flow of over 100 nL/min with an efficiency of 11 mJ/nL

당뇨병 의 최소침습 진단 및 약물 치료를 위한 방법론

학위논문 (박사) -- 서울대학교 대학원 : 공과대학 협동과정 바이오엔지니어링전공, 2021. 2. 최영빈.This dissertation is focused on design, fabrication and evaluation of a strip-type tear glucose sensor and an implantable magnetic pump for minimally-invasive diagnosis and drug therapy, respectively. Management of diabetes mellitus have been painful procedures to many patients, because the diagnosis included needled finger pricking with a lancet, and the drug therapy were conducted with needled injections. There have been research efforts to minimize the pain associated with the diabetes mellitus management, but still there are unmet drawbacks. Therefore, methodologies of minimally-invasive diagnosis and drug therapy are proposed in this study. First, a strip-type tear glucose sensor was developed for concurrent tear collection and measurement with a small tear volume. Current tear glucose measurement has drawbacks such as large tear sample volume, long tear collection time, discomfort to patients, and two-step procedure that require sample transfer from tear collector to measuring instruments. To resolve these issues, a highly-accurate strip-type electrochemical sensor was modified by reducing the volume of reaction chamber to 0.4 μl. Then the modified sensor and a 3D printed lid to ensure safety to the eye were assembled. The assembled sensor, or the tear-glucose device, could collect tear fluid sample within 2 seconds, and simultaneously measure tear glucose concentration accurately without sample transfer. Through animal experiments, a high correlation between tear glucose concentration and the blood glucose concentration were determined with the tear-glucose device. The Clarke error grid analysis suggested that the blood glucose concentration estimated from the tear glucose sensor showed acceptable accuracy compared to that measured with commercially available blood glucometer. In addition, an implantable magnetic pump enabled with on-demand bolus delivery of exenatide was developed. The magnetic pump could deliver a bolus of 11.4 ± 0.3 μg of exenatide for optimal exenatide delivery regimen. This magnetic pump was designed to be actuated with a patterned magnetic field, thus could prevent unintended actuations by a single household magnet. In addition, a flexible polyurethane drug container in the magnetic pump could resolve negative pressure issues that could occur in solid drug container. The magnetic pump could deliver up to 300 times without a drug replenishment. The absence of battery and the presence of refillable drug container enabled a semi-permanent usage of the magnetic pump. The magnetic pump showed a similar pharmacokinetic profile compared to the injection therapy. When implanted in type 2 diabetic animal models, the magnetic pump showed comparable efficacy to injection therapy, in terms of body weight change, food intake, glycemic control, insulin secretion, insulin sensitivity, gastric emptying rate, beta cell proliferation and adipocyte size reduction. Through these studies, it is concluded that the strip-type tear glucose sensor and the magnetically actuated pump developed herein could be suggested as methodologies to replace invasive finger pricking and injection therapy.많은 당뇨 병 환자들이 현재 채혈을 통한 진단 방법과 주사를 통한 약물 치료를 통해 혈당을 관리하고 있다. 이런 침습적인 진단 및 투약 방식은 환자들에게 많은 고통과 트라우마 굳은 살, 가려움증 및 염증 등의 부작용을 초래하는 문제점이 있다. 이를 해결하기 위해 본 논문에서는 당뇨 병 진단 및 약물치료를 위한 최소침습 방법론 을 제안하고자 한다. 먼저 채혈 진단 방식의 대안으로 눈물 내 당 농도, 즉 누당을 측정 하는 센서를 개발하였 다 누당은 혈당과 높은 상관관계를 보이는 까닭에 많은 진단 연구가 진행되었다. 그러나 많은 양의 눈물 샘플을 필요로 하며 이를 채취하는 시간이 길어져 환자에게 불편함과 고통을 야기하는 문제점이 있었다. 또한 눈물 샘플을 채취 장치에서 측정 장치로 옮기는 과정에서 발생하는 정확도의 하락과 불편함이 문제가 되었다. 이런 문제를 해결하기 위해 높은 정확도를 가지는 전기화학 센서를 개조하여 필요 눈물 양을 0.4 μl로 줄였으며, 3D 프린트 된 lid의 장착을 통하여 전안부 접촉 시에도 손상을 야기하지 않도록 하였다. 개조된 센서와 lid의 결합으로 구성된 tear-glucose device는 전안부에 접촉한 지 2 초 이내에 필요한 양의 샘플을 채취할 수 있었으며 채취와 동시에 누당 농도를 측정하였다. 동물 모델에 적용한 결과, tear-glucose device를 통해 혈당과 누당 간의 높은 상관관계를 확인할 수 있었다. 또한 Clarke error grid analysis결과, 개발된 tear-glucose device를 통해 계산된 혈당값이 이미 상용화된 혈당 측정기 대비 준수한 정확도를 보였음을 확인할 수 있었다. 다음으로 주사 약물 치료의 대안으로 이식형 약물전달 디바이스를 개발하였다. 현재 개발된 당뇨 병 관리용 이식형 약물전달 디바이스의 경우, 약물치료 regimen을 최적화하지 못하여 tachyphylaxis를 야기하거나 디바이스의 크기, 수명, 안전성에 문제가 있는 경우가 있었다. 이러한 문제를 해결하기 위해 패턴화된 자기력 구동 이식형 약물전달 펌프를 개발하였다. 본 펌프는 on-demand bolus 전달 방식을 통해 최적화된 약물치료 regimen을 구현하고, 배터리 대신 자기력 구동 방식을 사용해 디바이스의 크기, 수명 문제를 해결하고, 패턴화된 자기력을 사용함으로 안전성 문제를 해결하였다. 또한 폴리우레탄 약물저장소를 사용하여 고체 약물저장소에서 나타나는 음압으로 인한 방출 문제를 해결하였다. 본 펌프를 평가한 결과, 11.4 ± 0.3 μg의 exenatide를 약물 충전 없이 300 회 방출시킬 수 있었다. 동물 모델에서 평가한 결과 약력학 및 약동학에서 기존 주사 약물치료와 유사한 효과를 보였다. 본 연구를 통해 개발된 누당 측정 센서와, 자기력 구동 이식형 약물전달 펌프는 기존 사용되는 혈당측정기와 주사 약물치료 방법론과 유사한 효용성을 보이는 것을 확인하였다. 따라서 이는 침습적인 당뇨 병 의 진단 및 약물치료 방식의 대안으로 제시될 수 있을 것이라 기대 한다.Abstract ……………………………………………………………………… i Contents …………………………………………………………………… iv List of Tables ……………………………………………………………… vii List of Figures …………………………………………………………… viii Chapter 1. Introduction …………………………………………………… 1 1.1. Current management methodologies for diabetes mellitus……………. 1 1.2. Tear-based methodologies of minimally-invasive diagnosis for diabetes mellitus ……………………………………………………………………… 3 1.3. Implantable drug delivery device for minimally-invasive drug therapy for diabetes mellitus………………………………………………………………5 1.4. Current limitations and research aims ………………………………… 7 Chapter 2. Strip-type tear glucose sensor for concurrent tear collection and glucose measurement ………………………………………………… 9 2.1. Device design …………………………………………………………… 9 2.2. Methods ……………………………………………………………… 11 2.2.1. Lid ……………………………………………………………… 11 2.2.2. Strip-type glucose sensor ………………………………………… 14 2.2.3. In vitro evaluation ……………………………………………… 15 2.2.4. In vivo evaluation ……………………………………………… 17 2.2.5. Statistical analysis ……………………………………………… 18 2.3. Results ……………………………………………………………… 18 2.3.1. Tear-glucose device ……………………………………………… 18 2.3.2. In vitro performance evaluation ………………………………… 20 2.3.3. In vivo performance evaluation ………………………………… 20 2.3.4. In vivo safety evaluation ………………………………………… 26 2.4. Discussions …………………………………………………………… 28 Chapter 3. Implantable magnetic pump for bolus delivery of exenatide 33 3.1. Device design ………………………………………………………… 33 3.2. Methods ……………………………………………………………… 35 3.2.1. Materials ………………………………………………………… 35 3.2.2. Magnetic pump fabrication ……………………………………… 35 3.2.3. Magnetic design principles ……………………………………… 38 3.2.4. High-performance liquid chromatography measurements ……… 38 3.2.5. In vitro performance test ………………………………………… 38 3.2.6. Accelerated depletion test ……………………………………… 39 3.2.7. Stability evaluation of exenatide ………………………………… 39 3.2.8. Animal study …………………………………………………… 40 3.2.9. Glucose tolerance test …………………………………………… 43 3.2.10. Paracetamol absorption test …………………………………… 43 3.2.11. Histology and immunohistochemistry ………………………… 43 3.2.12. Statistical analysis ……………………………………………… 44 3.3. Results ………………………………………………………………… 45 3.3.1. Pump design and working principles …………………………… 45 3.3.2. In vitro performance test ………………………………………… 52 3.3.3. In vivo pharmacokinetic tests …………………………………… 57 3.3.4. In vivo pharmacodynamic tests ………………………………… 62 3.3.5. Effects on the pancreatic islets and adipose tissues ……………… 70 3.3.6. Biocompatibility assessment …………………………………… 77 3.4. Discussions …………………………………………………………… 82 Chapter 4. Conclusion and perspective ………………………………… 86 References ………………………………………………………………… 89 Abstracts in Korean ……………………………………………………… 97 Acknowledgment……………………………………………………… 100Docto

Design, Testing and Evaluation of Robotic Mechanisms and Systems for Environmental Monitoring and Interaction

Unmanned Aerial Vehicles (UAVs) have significantly lowered the cost of remote aerial data collection. The next generation of UAVs, however, will transform the way that scientists and practitioners interact with the environment. In this thesis, we address the challenges of flying low over water to collect water samples and temperature data. We also develop a system that allows UAVs to ignite prescribed fires. Specifically, this thesis contributes a new peristaltic pump designed for use on a UAV for collecting water samples from up to 3m depth and capable of pumping over 6m above the water. Next, temperature sensors and their deployment on UAVs, which have successfully created a 3D thermal structure map of a lake, contributes to mobile sensors. A sub-surface sampler, the “Waterbug” which can sample from 10m deep and vary buoyancy for longer in-situ analysis contributes to robotics and mobile sensors. Finally, we designed and built an Unmanned Aerial System for Fire Fighting (UAS-FF), which successfully ignited over 150 acres of prescribed fire during two field tests and is the first autonomous robot system for this application. Advisers: Carrick Detweiler and Carl Nelso

Development of a new biosensor array and lab-on-a-chip for portable applications using a label-free detection method

The detection and quantification of cardiac biomarkers in serum is crucial to diagnose patients in the early stage of a disease. The recent advances in microfluidics technology can improve diagnostics by reducing the application time and integrating several clinical analysis into a single, portable device called lab-on-a-chip (LOC). The development of such immunosensing LOC is a major thrust of the rapidly growing bionanotechnology industry. It involves a multidisciplinary research effort encompassing microfluidics, microelectronics and biochemistry. This thesis work focused on the development of immunoassays on microfabricated gold inter-digitated transducers (IDT) on silica and glass substrates. The concept of label-free, affinity-based biosensing is introduced with a special emphasis to impedance spectroscopy. Different protocols involving the covalent immobilization of cancer risk marker (human epidermal growth factor, hEGFR) and cardiac risk marker proteins C reactive protein (CRP), interleukin (IL6) and nicotinamide phosphoribosyltransferase (Nampt) single stranded deoxyribonucleic acid were investigated. For this, IDTs were fabricated using integrated circuit (IC) fabrication processes providing compatibility for the integration of electronic circuits, for single-chip and lab-on-a-chip biosensing applications. The thesis also involves development of a poly dimethylsiloxane (PDMS)-based fluidic system comprising on-chip actuated mechanism for multi-target immunosensing applications. The fluidic flow is controlled by an applied hydraulic pressure on the micropump. Label-free affinity type sensing was carried out using two different biological recognition elements (a) immunosensing approach using antibodies for hEGFR and IL-6 was employed and the function of the LOC was analyzed for detection of hEGFR and IL-6 as model analytes. A detection limit of 0.1ng/ml of hEGFR and IL-6 in serum was obtained without any signal amplification. (b) label-free affinity-based methodology using ssDNA aptamers specific for Nampt to develop an aptasensor and obtained a detection limit of 1 ng/ml in serum for Nampt, which is the most sensitive detection range with the application of the aptamer for Nampt